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The Genetic Architecture of Gliomagenesis–Genetic Risk Variants Linked to Specific Molecular Subtypes

1
Department of Radiation Sciences, Oncology, Umeå University, 901 87 Umeå, Sweden
2
Department of Medical Bioscience, Umeå University, 901 87 Umeå, Sweden
3
Department of Advanced Home Care, Linköping University and Department of Clinical and Experimental Medicine, Linköping University, 581 83 Linköping, Sweden
4
Department of Health Research and Policy (Epidemiology), Stanford University School of Medicine, Stanford, CA 94305, USA
5
Department of Medicine, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2019, 11(12), 2001; https://doi.org/10.3390/cancers11122001
Received: 28 October 2019 / Revised: 5 December 2019 / Accepted: 7 December 2019 / Published: 12 December 2019
(This article belongs to the Special Issue Tumors of the Central Nervous System: An Update)
Genome-wide association studies have identified 25 germline genetic loci that increase the risk of glioma. The somatic tumor molecular alterations, including IDH-mutation status and 1p/19q co-deletion, have been included into the WHO 2016 classification system for glioma. To investigate how the germline genetic risk variants correlate with the somatic molecular subtypes put forward by WHO, we performed a meta-analysis that combined findings from 330 Swedish cases and 876 controls with two other recent studies. In total, 5,103 cases and 10,915 controls were included. Three categories of associations were found. First, variants in TERT and TP53 were associated with increased risk of all glioma subtypes. Second, variants in CDKN2B-AS1, EGFR, and RTEL1 were associated with IDH-wildtype glioma. Third, variants in CCDC26 (the 8q24 locus), C2orf80 (close to IDH), LRIG1, PHLDB1, ETFA, MAML2 and ZBTB16 were associated with IDH-mutant glioma. We therefore propose three etiopathological pathways in gliomagenesis based on germline variants for future guidance of diagnosis and potential functional targets for therapies. Future prospective clinical trials of patients with suspicion of glioma diagnoses, using the genetic variants as biomarkers, are necessary to disentangle how strongly they can predict glioma diagnosis. View Full-Text
Keywords: glioma; IDH mutant; 1p/19q co-deletion; gliomagenesis; genotype phenotype; etiopathogenesis glioma; IDH mutant; 1p/19q co-deletion; gliomagenesis; genotype phenotype; etiopathogenesis
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Wu, W. .-Y.; Johansson, G.; Wibom, C.; Brännström, T.; Malmström, A.; Henriksson, R.; Golovleva, I.; Bondy, M.L.; Andersson, U.; Dahlin, A.M.; Melin, B. The Genetic Architecture of Gliomagenesis–Genetic Risk Variants Linked to Specific Molecular Subtypes. Cancers 2019, 11, 2001.

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